Sites of action of IL-1 in the development of fever and cytokine responses to tissue inflammation in the rat (original) (raw)

1997, British Journal of Pharmacology

The objective of the present study was to determine the sites of action of the cytokine, interleukin-1 (IL-1), in the febrile response to local in¯ammation in the rat, by comparing the importance of IL-1 in the local tissues, the circulation and the brain. This was achieved by injecting lipopolysaccharide (LPS, 100 mg kg 71) into a subcutaneous air pouch and testing the eects of blocking IL-1 action with the human recombinant interleukin-1 receptor antagonist (IL-1ra) injected either into the air pouch, intraperitoneally (1 mg kg 71 , 0+1 h, i.p.), or intracerebroventricularly (200 mg/rat, 0+1 h, i.c.v.). 2 To investigate the eect of IL-1ra on fever and the induction of local and circulating cytokines (IL-1 and IL-6), separate experiments were performed in which groups of animals were killed 1.5, 3 or 5 h after LPS injection. Plasma and pouch¯uid samples were collected for bioassay of IL-1 and IL-6. 3 Injection of LPS into the air pouch signi®cantly increased (1.58C) body temperature, local (air pouch) concentrations of bioactive IL-1 and IL-6, and circulating bioactive IL-6, compared to saline-treated controls. 4 Injection of IL-1ra into the pouch signi®cantly attenuated LPS fever (P50.001). This decrease in body temperature was associated with signi®cant inhibition of local IL-1 bioactivity 1.5 (96%), 3 (84%) and 5 h (72%), and in bioactive IL-6 in pouch lavage¯uid 1.5 (45%) and 5 h (35%), after LPS injection. The concentration of bioactive IL-6 in the plasma was signi®cantly reduced (39%) at 3 h, when temperature was approaching the maximal value. 5 Both systemic (i.p.) and central (i.c.v.) administration of IL-1ra signi®cantly attentuated LPS fever (P50.05). However, it had no eect on either local concentrations of bioactive IL-1 or IL-6, or circulating IL-6, at any of the sample points. 6 These data suggest that IL-1 is released locally, at the site of tissue in¯ammation and that it is an important mediator of the febrile response to local in¯ammation. The results also indicate that IL-1 produced locally may contribute to the production of IL-6 which is released into the circulation, and that IL-1 has important actions in the generation of fever at other sites, including the brain.